Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on methamphetamine, amphetamine and delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. Numerous attempts to obtain reliable self-administration behavior by laboratory animals with THC have been unsuccessful. In contrast, self-administration behavior has been successfully demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans. From these studies it would seem that marijuana has less potential for abuse than other drugs abused by humans. In one series of studies, we have demonstrated for the first time persistent intravenous self-administration behavior by squirrel monkeys for doses of THC comparable to those in marijuana smoke inhaled by humans. The THC self-administration behavior was comparable in intensity to that maintained by cocaine under identical conditions. Also, treatment with SR141716A, an antagonist of CB1 cannabinoid receptors, almost completely eliminated THC self-administration behavior, but did not reduce cocaine self-administration behavior. These findings suggest that marijuana has as much potential for abuse as drugs of abuse such as cocaine and heroin. The selective effects with the cannabinoid antagonist SR141716A indicate that this abuse potential is likely mediated by cannabinoid CB1 receptors in the brain. In another series of studies, the role of different neurotransmitter systems in the reinforcing effects of methamphetamine is being evaluated in rats trained to i.v. self-administer methamphetamine. Our recent focus is on histaminergic influences. Although centrally applied histamine enhances locomotor activity, it can attenuate locomotor stimulation induced by methamphetamine, which is in line with some other studies suggesting that histamine exerts a negative effect on dopaminergic tonus. This negative effect may be due to stimulation of histamine H3 heteroreceptors located on dopaminergic neurons. H3 receptors are autoreceptors on histaminergic neurons with a negative feedback role in histamine release. However, these receptors are also localized on non-histaminergic neurons, including dopaminergic neurons and high densities of histamine H3 receptors are found in dopaminergic brain areas such as the nucleus accumbens, striatum and substantia nigra in both animals and humans. We have demonstrated that the discriminative-stimulus effects of methamphetamine are greatly enhanced by thioperamide, a selective histamine H3 antagonist, and that thioperamide dose-dependently decreases i. v. self-administration of an intermediate dose of methamphetamine in rats but increases self-administration of a low methamphetamine dose which is normally not self-administered, suggesting a left-ward shift in the methamphetamine dose-response curve. Thioperamide is, however, not itself self-administered and does not reinstate drug-seeking behavior. In microdialysis studies we have now demonstrated that thioperamide can markedly potentiate the increases in dopamine release in the shell of the nucleus accumbens produced by i. v. injection of methamphetamine, suggesting involvement of histamine H3 receptors on dopaminergic terminals in neurochemical processes thought to underly reward mechanisms.